Physiology of acid secretion
Parietal cells are located in the body of the stomach and secrete hydrochloric acid (HCl) into the lumen.
- Water and CO₂ are combined to produce hydrogen (H+) ions and HCO₃ ions by the action of the carbonic anhydrase enzyme.
- H+ is transported to the lumen of the stomach via the H+/K+ ATPase pump.
- HCO₃ is exchanged for chloride (Cl−) ion.
- H+ and Cl− combine to form the final product: HCl
Receptors and regulation
Acid production is stimulated by:
- Acetylcholine → muscarinic receptors
- Histamine release by enterochromaffin-like (ECL) cells → H₂ receptors
- Gastrin release by gastrin cells → cholecystokinin-2/cholecystokinin-B receptors
Common medication classes used to control gastric acid secretion include:
- Proton pump inhibitors (PPIs)
- H₂ receptor antagonists
Proton pump inhibitors are a group of drugs irreversibly inhibiting the H+/K+ ATPase pump in gastric parietal cells.
- Composed of 2 moieties:
- Weak bases
Mechanism of action
- Administered as a prodrug → concentrated in secretory canaliculi of the parietal cell
- Converted to an active form (a sulfonamide cation) → covalently binds to the H+/K+ ATPase pump
- Causes irreversible inhibition → prevents movement of H+ into the gastric lumen → ↓ acid secretion
- Inhibits both basal acid output and meal-stimulated output
- The most common route of administration is oral, but the medications can also be given intravenously.
- Inactive prodrugs
- Acid labile → formulated as acid-resistant, enteric-coated tablets or capsules
- Pass through the stomach → absorbed in the alkaline intestinal lumen
- Bioavailability is ↓ by the presence of food and should be administered 30–60 minutes prior to food intake.
- Readily cross into acidified areas (e.g., the lumen of the parietal cell gland)
- The serum half-life is short (called “hit-and-run” drugs because the duration of action is prolonged by approximately 24 hours).
- 3–4 days for maximum effect
- Rapid, hepatic 1st-pass metabolism
- Cytochrome P450 enzymes:
- Dose reduction is required in severe liver disease.
- Renal (primary)
- Abdominal pain
- Nutritional side effects on prolonged therapy:
- Malabsorption of vitamin B12
- ↓ Calcium absorption → ↑ risk of fracture in elderly
- Iron deficiency
- ↑ Risk of infection:
- Clostridioides difficile
- Bacterial gastroenteritis
- Community-acquired and nosocomial pneumonia
- Microscopic colitis
- Atrophic gastritis
- Acute interstitial nephritis
- Drug-induced lupus
- Interactions due to CYP450 enzymes:
- ↓ Activity:
- Clopidogrel requires CYP219 for action → concurrent use of PPI can ↓ anticoagulant and antiplatelet action
- PPIs inhibit the metabolism of:
- ↓ Activity:
- ↓ Gastric acidity can alter the absorption of medications:
- Amphetamines (e.g., dextroamphetamine)
H₂ Receptor Antagonists
H₂ receptor antagonists (also known as H₂ blockers) are competitive inhibitors of H₂ receptors in parietal cells, which aid in the reduction of acid secretion.
- Histamine-based molecules
- Ranitidine (withdrawn from the market in the United States in 2020)
Mechanism of action
- Competitive, reversible antagonists of H2 receptors on gastric parietal cells:
- Histamine is blocked from binding to the receptor → ↓ cAMP → ↓ protein kinase activation
- ↓ Activation of H+/K+ ATPase → ↓ acid secretion
- Additional consequence: ↓ effect of acetylcholine and gastrin on parietal cells
- ↓ Basal output and meal-stimulated output
- Given in oral and IV preparations
- Well absorbed
- Not affected by food
- Onset of action: 30–60 minutes
- Half-life range: 1–4 hours
- The volume of distribution decreases in the elderly.
- Crosses the placenta and is secreted in breast milk
- Hepatic 1st-pass metabolism
- Some are metabolized by the cytochrome P450 system.
- Elimination: renal
- Peptic ulcer disease (PUD)
- Stress-ulcer prophylaxis
- Prevention of aspiration pneumonia
- Anaphylaxis (in combination therapy)
Adverse drug reactions
- CNS effects (associated with IV administration):
- Cardiovascular (associated with rapid IV administration):
- Reproductive effects (cimetidine-related):
- Impotence in men
- Galactorrhea in women
- Vitamin B12 deficiency (with long-term use)
The medications can be potent inhibitors of cytochrome P450 (particularly cimetidine), resulting in ↑ plasma concentrations of:
- Many other drugs
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